Cumulative Anthracycline Dose Research Articles

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study.

Background: Acute leukemias are the most frequent malignancies in children. Advances in treatment have improved the overall survival to 80%. Almost 10% of children with cancer develop clinical cardiac toxicity. Total anthracycline cumulative dose is a risk factor for early-onset cardiotoxicity.Objective: To describe the incidence of early-onset cardiotoxicity in children with acute leukemia treated with chemotherapy.Methods: A prospective descriptive study of patients >1 y and <18 years diagnosed with acute leukemia. Assessed with electrocardiograma, echocardiography, and blood biomarkers at diagnosis and during the follow-up.Results: 94 patients with acute lymphoblastic leukemia and 18 with acute myeloid leukemia were included. 20 patients (17.9%) developed early-onset cardiotoxicity. Statistically significant data was seen after anthracycline dose >150 mg/m2, between the first echocardiographic evaluation and posterior analyses in the left ventricular fraction ejection with Teicholz p 0.05, Simpson p 0.018 and GLS p 0.004. In this study, there was no relation between blood biomarkers and cardiotoxicity.Conclusions: Cancer therapeutic-related cardiac dysfunction is related to anthracycline cumulative dose. In this study, echocardiographic follow-up was useful to predict risk factors for early cardiac dysfunction.

Assessment of Subclinical Deterioration of Right Ventricular Function by Three-Dimensional Speckle Tracking Echocardiography in Breast Cancer Patients Undergoing Anthracycline-Based Chemotherapy.

ObjectiveThis study was aimed at assessing the longitudinal strain changes of RV function using three-dimensional speckle tracking echocardiography (3D STE) in breast cancer patients receiving anthracycline chemotherapy.Patients and MethodsA total of 95 women with breast cancer receiving epirubicin (360 mg/m2) underwent 3D STE at baseline, the end of chemotherapy and 12 months after chemotherapy. 3D STE assessment included RV ejection fraction (EF), LV global longitudinal strain (GLS), RV GLS, and RV free wall longitudinal strain (RV FWLS). Meanwhile, serum hs‐cTnI and NT-proBNP were measured. Chemotherapy-related cardiac dysfunction (CTRCD) was defined as an absolute decrease in 3D LVEF > 10% to a value <50%, while a percent reduction of 3D LV GLS > 15% indicated subclinical CTRCD.ResultsSubclinical CTRCD occurred in 10 (10.5%) patients during follow-up. Compared to baseline, the 3D GLS of LV and GLS and FWLS of RV decreased significantly at 12months after chemotherapy (all p<0.01). Variations of 3D RV GLS and RV FWLS had a good discrimination for predicting subclinical CTRCD. The variation of 3D RV FWLS was the only independent predictor of subclinical CTRCD (OR, 1.37; 95% CI, 1.12–2.87; p = 0.028) in multivariate analysis. The cutoff value with −17.5% of 3D RV FWLS variation had a high predictive accuracy for subclinical CTRCD, with an AUC of 0.74, 80.5% sensitivity and 65.8% specificity. The association between 3D RV FWLS and the cumulative dose of anthracyclines was calculated by Spearman’s test (r = −0.71, p < 0.001).ConclusionLongitudinal strain analysis by 3D STE allows the identification of subclinical RV dysfunction when conventional indices of RV function are unaffected. 3D RV FWLS was superior to other parameters in early detection of the development of CTRCD in breast cancer patients receiving epirubicin therapy.

How to identify anthracycline-induced cardiotoxicity early and reduce its clinical impact in everyday practice

Discovered in the 1960s, anthracyclines are still among the most widely used chemotherapy drugs, but are associated with cardiotoxicity. To date, the main strategies that seem to be effective in reducing its incidence and severity include screening and treating preexisting cardiovascular risk factors, limiting the cumulative anthracycline dose with a preference for less toxic analogues, and administering cardioprotective drugs as early as possible after its diagnosis. A better understanding of the underlying mechanisms and greater refinement of the diagnostic tools at our disposal has led to considerable progresses in the detection of this serious side effect at a preclinical stage, allowing for prompt intervention. However, despite increasing efforts to identify early predictors of cardiotoxicity and growing evidence of the importance of cardiac biomarkers for this purpose, large randomized multicenter clinical trials are still lacking and so there is still no scientific agreement on the best approach for early diagnosis. Nonetheless, dosing troponin at each chemotherapy cycle and initiating, when it increases above the threshold, a therapy with renin-angiotensin-aldosterone system inhibitors and/ or β-blockers has proved to be an effective strategy in reducing the progression of microscopic myocardial damage into left ventricular remodelling and clinically evident cardiotoxicity.

Adolescents and young adult acute myeloid leukemia outcomes at pediatric versus adult centers: A population-based study.

Adolescents and young adult (AYA) acute myeloid leukemia (AML) outcomes remain poor. The impact of locus of care (LOC; adult vs pediatric) in this population is unknown. The IMPACT cohort comprises detailed data for all Ontario, Canada, AYA aged 15-21 years diagnosed with AML between 1992 and 2012, linked to population-based health administrative data. We determined the impact of LOC on event-free survival (EFS) and overall survival (OS), treatment-related mortality (TRM), and relapse/progression. Among 140 AYA, 51 (36.4%) received therapy at pediatric centers. The five-year EFS and OS for the whole cohort were 35.0% ± 4.0% and 53.6% ± 4.2%. Cumulative doses of anthracycline were higher among pediatric center AYA [median 355mg/m2 , interquartile range (IQR) 135-492vs 202mg/m2 , IQR 140-364; P=0.003]. In multivariable analyses, LOC was not predictive of either EFS [adult vs pediatric center hazard ratio (HR) 1.3, 95% confidence interval (CI) 0.8-2.2, P=0.27] or OS (HR 1.0, CI 0.6-1.6, P=0.97). However, patterns of treatment failure varied; higher two-year incidence of TRM in pediatric centers (23.5% ± 6.0%vs.10.1% ± 3.2%; P=0.046) was balanced by lower five-year incidence of relapse/progression (33.3% ± 6.7%vs 56.2% ± 5.3%; P=0.002). AYA AML survival outcomes did not vary between pediatric and adult settings. Causes of treatment failure were different, with higher intensity pediatric protocols associated with higher TRM but lower relapse/progression. Careful risk stratification and enhanced supportive care may be of substantial benefit to AYA with AML by allocating maximal treatment intensity to patients who most benefit while minimizing the risk of TRM.

Early surveillance of anthracycline induced cardiotoxicity in children using echocardiography and biomarkers: A prospective study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CIHR Background Anthracyclines, which are commonly used in cancer treatment can induce myocardial damage, result in heart failure during treatment and have cardiac effects even decades after treatment. Monitoring of cardiotoxicity during treatment is largely based on the use of echocardiographic functional markers like ejection fraction and more recently myocardial strain imaging. Some studies have also looked at the utility of biomarkers like troponin and BNP. The utility of this surveillance strategy remains controversial as larger prospective studies are lacking. Purpose The aim of this study was to prospectively describe the impact of anthracycline treatment on echocardiographic functional parameters and cardiac biomarkers (high sensitivity troponin T and NT-Pro BNP) during the treatment period and twelve months after completion of treatment. In the current study we wanted to look at whether monitoring parameters during treatment were predictive of left ventricular function 12 months after treatment. Methods This was a prospective multi-centre nested case-control study of 256 children diagnosed with cancer requiring anthracycline therapy. Baseline functional echocardiographic parameters and cardiac biomarkers were obtained prior to starting anthracycline therapy, during the treatment protocol, and 12 months after treatment completion. Patients were assigned to one of two comparison groups based on the fractional shortening at the12-month echocardiogram: patients in group 1 had normal fractional shortening, (FS ³ 28%) while patients in group 2 had reduced fractional shortening (FS &amp;lt; 28%). Results A total of 917 echoes were performed, 376 of these occurred during the treatment period. FS was reduced in 27 (7%) of echoes obtained during the treatment period with 22 patients developing new onset dysfunction. Twelve months after treatment completion 232 patients had normal FS (Group 1), while 24 patients showed reduced FS (Group 2). Both groups had normal systolic function and cardiac biomarkers at baseline, however patients in group 2 were older at diagnosis (13.2 years (11.8-16) vs 6.5 years (3.4-13.2), p = 0.003) and received a higher cumulative anthracycline dose (200 mg/m2 (143-318) vs 125 mg/m2 (75-200), p= 0.005). One third (8/24) of patients in group 2 had at least 1 abnormal echo during the treatment period compared to 7% (16/232) in the normal group P &amp;lt; 0.001. The proportion of patients with at least one abnormal biomarker during this period however, was similar between groups. Conclusion(s) Patients receiving higher accumulative anthracycline doses and those with abnormal FS during the treatment period are at higher risk of having reduced cardiac function 12 months after treatment. High sensitivity troponin and NT-Pro BNP levels during the treatment period fail to discriminate patients at risk of developing early reduced systolic function. The relationship of these early results to long term cardiac function remains to be demonstrated.

Cardiovascular and Thyroid Late Effects in Pediatric Patients with Hodgkin Lymphoma Treated with Abvd Protocol

Background: Long-term Hodgkin Lymphoma (HL) survivors are at risk of developing a range of therapy-related complications that may present 10 -15 years after treatment. The goal of this study is to estimate the frequency of cardiovascular diseases and thyroid abnormalities in HL survivors and to determine the contributing risk factors. Methods: We performed a cross-sectional study on 208 HL survivors who were treated at the National Cancer Institute, Cairo University, or at the Children Cancer Hospital Egypt with ABVD chemotherapy ± radiotherapy with a minimum of five years follow up. Findings: The cumulative incidence of cardiac toxicity (CT) at five and nine years were 18·7% ± SD 2·7 and 43·3% ± SD 4·4, respectively. Preexisting cardiac abnormalities, cumulative anthracycline dose, and end of treatment cardiac status are strong predictors for late cardiotoxicity. Hypertension was observed in about 31% of HL survivors. Young age and obesity at the time of treatment are important factors for hypertension. Thyroid abnormalities developed with a 5-year cumulative incidence of 2%± SD 1 while at 9-years the cumulative incidence was 27·9%± SD 4·5. Thyroid dysfunction was observed in 21·2% and thyroid tumors in 1·6%. Subclinical hypothyroidism was the most common thyroid abnormality after HL treatment. Neck radiation therapy and the volume of thyroid gland exposed to radiation are important risk factors. Interpretation: Cardiotoxicity, hypertension, and thyroid dysfunction are frequent late effects following the ABVD regimen especially if combined with radiation therapy. Funding: None to declare. Declaration of Interest: The authors declare that there is no conflict of interest. Ethical Approval: The study was approved by the institutional review board of the NCI-Cairo University and the scientific medical advisory committee of CCHE.

Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM Group report

The purpose of our study was to investigate the efficacy of an acute lymphoblastic leukemia (ALL)-type treatment with moderate-dose, prophylactic cranial irradiation and without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). From April 1990 to March 1995, 105 evaluable patients, 1.1 to 16.4 years of age, with T-LBL were enrolled in study NHL-BFM 90 (non-Hodgkin's lymphoma-Berlin-Frankfurt-Munster 90). They received an 8-drug induction over 9 weeks followed by an 8-week consolidation including methotrexate (MTX) 5 g/m(2) x 4. Patients with stage I (n = 2) and II (n = 2) continued with maintenance therapy (6-mercaptopurine daily and MTX weekly, both orally) until a total therapy duration of 24 months. Patients with stage III (n = 82) and IV (n = 19) received an 8-drug intensification over 7 weeks and cranial radiotherapy (12 Gy for prophylaxis) after consolidation, followed by maintenance. Residual tumor after induction had to be resected. Patients received intensified chemotherapy if tumor regression on day 33 of induction was less than 70% or when vital residual tumor was present after the complete induction phase. With a median follow-up of 4.5 years, the estimated event-free survival at 5 years is 90% (95% confidence interval, 82%-100%). Events were 1 early death, 8 tumor failures, and 1 secondary acute myeloid leukemia. A total of 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to less than 70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. We conclude that, with intensive ALL-type chemotherapy including moderate cumulative doses of anthracyclines 240 mg/m(2) and cyclophosphamide (3 g/m(2)) and moderate-dose prophylactic cranial irradiation but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. (Blood. 2000;95:416-421)

Excellent Survival Outcomes of Pediatric Patients With Acute Myeloid Leukemia Treated With the MASPORE 2006 Protocol

PurposeTo determine the prognostic factors in pediatric patients with acute myeloid leukemia (AML) and to assess whether their outcomes have improved over time. Patients and MethodsSixty-two patients with AML excluding acute promyelocytic leukemia were retrospectively analyzed. Patients in the earlier cohort (n = 36) were treated on the Medical Research Council (MRC) AML12 protocol, whereas those in the recent cohort (n = 26) were treated on the Malaysia–Singapore AML protocol (MASPORE 2006), which differed in terms of risk group stratification, cumulative anthracycline dose, and timing of hematopoietic stem-cell transplantation for high-risk patients. ResultsSignificant improvements in 10-year overall survival and event-free survival were observed in patients treated with the recent MASPORE 2006 protocol compared to the earlier MRC AML12 protocol (overall survival: 88.0% ± 6.5% vs 50.1% ± 8.6%, P = .002; event-free survival: 72.1% ± 9.0 vs 50.1% ± 8.6%, P = .045). In univariate analysis, patients in the recent cohort had significantly lower intensive care unit admission rate (11.5% vs 47.2%, P = .005) and numerically lower relapse rate (26.9% vs 50.0%, P = .068) compared to the earlier cohort. Multivariate analysis showed that treatment protocol was the only independent predictive factor for overall survival (hazard ratio = 0.21; 95% confidence interval, 0.06-0.73, P = .014). ConclusionOutcomes of pediatric AML patients have improved over time. The more recent MASPORE 2006 protocol led to significant improvement in long-term survival rates and reduction in intensive care unit admission rate.

Is there scope for better individualisation of anthracycline cancer chemotherapy?

Anthracyclines are used to treat solid and haematological cancers, particularly breast cancers, lymphomas and childhood cancers. Myelosuppression and cardiotoxicity are the primary toxicities that limit treatment duration and/or intensity. Cardiotoxicity, particularly heart failure, is a leading cause of morbidity and mortality in cancer survivors. Cumulative anthracycline dose is a significant predictor of cardiotoxicity risk, suggesting a role for anthracycline pharmacokinetic variability. Population pharmacokinetic modelling in children has shown that doxorubicin clearance in the very young is significantly lower than in older children, potentially contributing to their higher risk of cardiotoxicity. A model of doxorubicin clearance based on body surface area and age offers a patient-centred dose-adjustment strategy that may replace the current disparate initial-dose selection tools, providing a rational way to compensate for pharmacokinetic variability in children aged <7 years. Population pharmacokinetic models in adults have not adequately addressed older ages, obesity, hepatic and renal dysfunction, and potential drug-drug interactions to enable clinical application. Although candidate gene and genome-wide association studies have investigated relationships between genetic variability and anthracycline pharmacokinetics or clinical outcomes, there have been few clinically significant reproducible associations. Precision-dosing of anthracyclines is currently hindered by lack of clinically useful pharmacokinetic targets and models that predict cumulative anthracycline exposures. Combined with known risk factors for cardiotoxicity, the use of advanced echocardiography and biomarkers, future validated pharmacokinetic targets and predictive models could facilitate anthracycline precision dosing that truly maximises efficacy and provides individualised early intervention with cardioprotective therapies in patients at risk of cardiotoxicity.

Successful Therapy Reduction in NCI Standard Risk (SR) Highly Favorable Subgroup of Childhood Acute Lymphoblastic Leukemia

Background: Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood; it is curable in 80-90% of patients. Current efforts focus on therapy guided by sensitive and specific methods of minimal residual disease (MRD) monitoring, tailoring the type and intensity of chemotherapeutic agents to improve cure rates, quality of life and decrease morbidity. We sought to study the outcome of low risk (LR) ALL treated per modified St Jude total XV Study. Methods: We adopted the modified St Jude total XV study ,B-cell precursor patients with age between 1 and 10 years and presenting leukocyte count &amp;lt;50×10^9/L, leukemic cell DNA index ≥1.16, or TEL-AML1 fusion are classified to have low-risk ALL, provided that they do not have testicular or central-nervous-system (CNS-3) leukemia, hypodiploidy (&amp;lt;45 chromosomes), E2A-PBX1 fusion, or MLL rearrangement, and have a treatment response at day 15 by minimal residual disease (MRD) of &amp;lt;5% and at day 46 of remission-induction &amp;lt;0.01%. We further identified a subgroup of (LR) ALL; defined by presenting age between 2 and 6 years, leukocyte count of &amp;lt;10x 10^9/L and MRD of &amp;lt;0.01% at day 15 of remission induction as Very Low Risk ALL (VLR). Patients with St Jude Low Risk (LR) ALL were treated per St Jude total XV study with several modifications: On 2007; doxorubicin was omitted from reinduction II to lower the total cumulative dose of anthracycline to 80 mg/m2, pulses of dexamethasone and vincristine were stopped at week 72 of maintenance instead of 100. On 2012; for patients identified as VLR; pulses of vincristine /dexamethasone were stopped at week 52 and HDMTX given at week 10 and 12 of maintenance therapy was omitted, frequency of triple Intrathecal chemotherapy remained unchanged (13-18) for LR ALL based on CNS status. Results: We reviewed 184 patients with (LR) between May 2006 to Feb 2018, (the median age at diagnosis, 7.3 years; range, 1.5-9.8). Eighty-two patients (45%) and 102 patients (55%) were treated as VLR and LR ALL respectively. The only significant difference in patients of two groups were age at diagnosis 2-6 years(VLR, 100%; LR, 46%; p&amp;lt;0.001), initial count &amp;lt;10x 10^9/L (VLR, 100%; LR, 65%; p&amp;lt;0.001) and MRD at day 15&amp;lt;0.01%(VLR, 100%; LR, 61%; p&amp;lt;0.001). At median follow up of (48 months; range, 17 to 157), in the subgroups of NCI standard risk defined above; as very low risk(VLR) ALL and low risk (LR) ALL, the 5-year EFS were 92%±3.4; 85%±4 (p=0.12), and the 5-year OS were 98%±1.7; 93%±3.3 (p=0.2) respectively. Conclusion: Chemotherapy was substantially reduced safely in subgroup of children with low risk ALL who were selected on the basis of presenting age, leukocyte count and undetectable MRD levels early at day 15 and at day 46 of remission induction without jeopardizing the survival rate. Patients with St Jude LR ALL maintained outstanding outcomes despite reduction of chemotherapy. Disclosures No relevant conflicts of interest to declare.

Cardiac Morbidity in Adolescents and Young Adult Survivors of Hodgkin Lymphoma

Cardiac Morbidity in Adolescents and Young Adult Survivors of Hodgkin Lymphoma

Importance of familial predisposition to heart failure to the risk of anthracycline related cardiotoxicity: a nationwide study

Abstract Background/Introduction Anthracycline-based chemotherapy has improved the prognosis in cancer and hematological malignancies but is associated with the development of heart failure (HF). Besides well-known cardiac risk factors and cumulative dose of anthracycline, recent research has suggested that genetic variations associated with cardiomyopathies may increase the risk of HF associated with anthracycline. However, the importance of familial predisposition for the risk of developing anthracycline associated cardiotoxicity is unknown. Purpose To evaluate the risk of anthracycline related HF in patients with vs. without a first-degree relative with HF. Methods In the nationwide Danish registries, patients treated with anthracycline from 2004–2016 were identified. Primary outcome was a subsequent diagnosis of HF. Follow-up was 10 years or December 31, 2017. Familial relations were identified in the Danish Family Registry, which hold all persons born since 1942. Exposure was a first-degree biological relative (parent or sibling) with a diagnosis of HF. Risk of HF was evaluated in a cumulative incidence function with death as competing event and in a Fine and Grey model adjusted for age, sex, prevalent ischemic heart disease, atrial fibrillation, hypertension and chronic obstructive pulmonary disease. Results A total of 11.651 patients (mean age 48.0 (SD±8.6), 12.2% male gender) were evaluated after exclusion of 46 with pre-anthracycline HF. Mean follow-up was 4.4 years (SD±2.9). In the group with a first-degree relative with HF (n=1.608) 35 patients (2.2%) was diagnosed with HF vs. 133 (1.3%) in the group without a first-degree relative with HF (n=10.043) corresponding to incidence rates per 1000 patient years of 5.2 (95% CI: 3.8–7.3) vs. 3.0 (95% CI: 2.5–3.5). The cumulative incidence of HF was higher in the first-degree relative HF group (Figure 1a), yielding an adjusted hazard ratio of 1.53 (95% CI: 1.05–2.24, p=0.03) for HF associated with anthracycline. All-cause mortality showed a trend towards higher risk in the later 5 years of follow-up in the first-degree relative HF group with a 10-year risk of 32.4% (95% CI: 28.4–36.5) vs. 26.1% (95% CI: 24.9–27.4) but no significant difference in the Kaplan-Meier estimate (p=0.08) (Figure 1b). Conclusion In this nationwide register-based study having a first-degree relative with HF was associated with a small but increased risk of anthracycline related HF, yielding attention towards the family predisposition, when estimating the risk of cancer therapy related cardiotoxicity. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Odense University Hospital

The possible role of genetic testing in the early identification of patients at increased risk of developing anthracycline-induced cardiotoxicity

Abstract Background In the last years prognosis of cancer patients (pts) has been improved, but the develop of cardiotoxicity (CTX) in pts with low CV risk treated with cumulative doses of Anthracycline (ANT) considered safe, led to investigate the possible role of the genetic profile in the onset of CTX. Purpose To study the role of some single nucleotide polymorphisms (SNPs) as predictive genetic markers of individual susceptibility to CTX induced by anticancer treatment. Methods We have enrolled women with non-metastatic breast cancer who had to start a therapy with ANT. The presence of a known heart disease, a previous mediastinal irradiation and a previous treatment with ANT, were the main exclusion criteria. All pts underwent complete cardiological evaluation (ECG, echo) before the beginning of the therapy (T0), after each ANT cycle and every 3 months up to 1 year of follow-up after the end of treatment. During each visit, we performed the determination of troponin I (TnI) and NT-proBNP. The genetic profile of each pts was also investigated, analyzing 6 SNPs belonging to 3 different genes (two for each genes) coding for enzymes or enzyme systems involved in the metabolism of ANT. DNA extraction from blood samples was performed using the QIAamp DNA Mini kit (QIAGEN). The DNA extracted was genotyped (by performing TaqMan SNP Genotyping assays) identifying 3 possible variants for each SNPs: homozygosity for the protective and “at risk” variant and heterozygosity. Results 179 pts finished the follow-up and from the analysis of the trend of biomarkers we found that 53 pts (30%) showed a significant increase in TnI (&amp;gt;0.04ng/mL) or less than this cut-off but persistently &amp;gt;0.015ng/mL in at least 2 measurements (“TnI+ group”), in the remaining 126 pts the TnI remained non-measurable (“TnI− group”); 76 pts (43%) showed NT-proBNP values ≥125 ng/L in at least two consecutive determinations (“NT-proBNP + group”),in the remaining 57% of pts this increase was not detected (“NT-proBNP - group”). Comparing “TnI+ group” to “TnI− group” we observed that only the genotyping of the SNPs rs1149222 (G/T) belonging to the ABCB4 gene is distributed differently in the two groups, in particular the homozygosity for the “at risk” variant (G/G) was present in 13% of the pts of the “TnI+ group” vs 5% in the “TnI− group” (p 0.06). The results of the comparison of “NT-proBNP+ group” vs “NT-proBNP− group”, showed that the genotyping of the SNPs rs6759892 (G/T) belonging to the UGT1A6 gene was distributed differently, the homozygosity for the “at risk” variant (G/G) was present in 28% of the “NT-proBNP+ group” vs 17% in the “NT-proBNP− group” (p 0.07). Conclusion Together with the baseline clinical evaluation, genetic markers could contribute to the early identification of pts at high risk of developing CTX especially following treatment with ANT and they could support future therapeutic decisions and the planning of taylored strategies for the prevention of the CTX development. Funding Acknowledgement Type of funding source: None

Long-term echocardiographic assessment of descendants of gestational breast cancer patients exposed to anthracycline-based chemotherapy

Abstract Background Breast cancer is the most common cancer in women and the leading cause of cancer death in women. Although gestational breast cancer (GBC) accounts only for a small amount of diagnosis, the incidence is increasing due to delayed childbearing. Treating GBC is a significant challenge, having to maintain a balance between effective treatment for the patient and safety for the descendants. Anthracycline-based chemotherapy (AC) remains to be the systemic treatment of choice in many GBC patients. Although AC in GBC appears to be safe for the descendants, data on the long-term cardiotoxic effects of AC are scarce. Purpose To evaluate long-term cardiotoxicity on descendants of GBC patients exposed to AC during pregnancy or breastfeeding. Methods We retrospectively recruited descendants of GBC patients and classified them according to AC exposure (case group and non-exposed control group). We performed a thorough echocardiographic assessment. Results We identified 7 GBC patients that received AC during pregnancy (n=6) or breastfeeding (n=1). All of them were diagnosed during the second or third trimester. Median cumulative anthracycline dose was 508mg/m2. A total of 8 cases and 5 controls were recruited. Median age at echocardiographic assessment was 10 years in cases and 8 years in controls. None of them had known prior cardiac disease. Echocardiographic parameters were within normal values in both groups (Table 1). Conclusion A long-term echocardiographic assessment showed no abnormalities in a series of descendants of GBC exposed to AC during pregnancy or breastfeeding. This study may contribute to a better understanding of the safety for the descendants of AC during pregnancy or breastfeeding. Funding Acknowledgement Type of funding source: None

Red Blood Cell Distribution Width Is a Predictive Factor of Anthracycline-Induced Cardiotoxicity.

Background: Red blood cell distribution width (RDW) is associated with prognosis in widespread cardiovascular fields, but little is known about relationship with the onset of cancer therapeutics-related cardiac dysfunction (CTRCD).Objectives: The purpose of this study was to assess whether RDW could predict the onset of CTRCD by anthracycline.Methods: Consequential 202 cancer patients planed for anthracycline treatment were enrolled and followed up for 12 months. The patients were divided into 2 groups based on the median value of baseline RDW before chemotherapy [low RDW group, n = 98, 13.0 [12.6–13.2]; high RDW group, n = 104, 14.9 [13.9–17.0]]. Cardiac function was assessed serially by echocardiography at baseline (before chemotherapy), as well as at 3, 6, and 12 months after chemotherapy with anthracycline.Results: Baseline left ventricular end systolic volume index and ejection fraction (EF) were similar between two groups. After chemotherapy, EF decreased at 3- and 6-month in the high RDW group [baseline, 64.5% [61.9–68.9%]; 3-month, 62.6% [60.4–66.9%]; 6-month, 63.9% [60.0–67.9%]; 12-month, 64.7% [60.8–67.0%], P = 0.04], but no change was observed in low RDW group. The occurrence of CTRCD was higher in high RDW group than in low RDW group (11.5 vs. 2.0%, P = 0.008). When we set the cut-off value of RDW at 13.8, sensitivity and specificity to predict CTRCD were 84.6 and 62.0%, respectively. Multivariable logistic regression analysis revealed that baseline RDW value was an independent predictor of the development of CTRCD [odds ratio 1.390, 95% CI [1.09–1.78], P = 0.008]. The value of net reclassification index (NRI) and integrated discrimination improvement (IDI) for detecting CTRCD reached statistical significance when baseline RDW value was added to the regression model including known risk factors such as cumulative anthracycline dose, EF, albumin, and the presence of hypertension; 0.9252 (95%CI 0.4103–1.4402, P < 0.001) for NRI and 0.1125 (95%CI 0.0078–0.2171, P = 0.035) for IDI.Conclusions: Baseline RDW is a novel parameter to predict anthracycline-induced CTRCD.

Sperm DNA integrity in adult survivors of paediatric leukemia and lymphoma: A pilot study on the impact of age and type of treatment

Male childhood cancer survivors (CCS) show reduced fertility, mostly due to low sperm count. The links between DNA damage caused by cancer and its treatment, pubertal stage at diagnosis and future infertility are still unclear. This Canadian pilot study analysed reproductive parameters and sperm characteristics in adult survivors of childhood leukaemia and lymphoma, divided into 2 groups according to whether cancer diagnosis occurred before or after puberty. They were compared to age-matched men with no history of cancer. No differences were observed in mean serum testosterone and FSH levels, but 4 CCS had FSH levels >8 U/ml. No differences in average sperm count or motility were observed across groups, but 5 of the 13 CCS were affected by azoo/oligozoospermia, regardless of the time at cancer diagnosis. Analysis of sperm chromatin and DNA integrity revealed no differences among the groups. The authors observed a significant negative correlation between sperm count and the cumulative dose of alkylating agent, determined by the cyclophosphamide equivalent dose, and a strong positive correlation between the cumulative dose of anthracyclines and the DNA fragmentation index. A limitation of the study is the small sample size, which makes it difficult to generalize the results. It is noteworthy that both groups of CCS had a similar prevalence of azoo/oligozoospermia, supporting the hypothesis that the prepubertal testis is not protected from damage in children who undergo cancer treatment.

Subclinical Heart Injury in Patients Receiving Hypofractionated Radiotherapy after Breast Conserving Surgery: An Analysis of Prospective Study

To evaluate the incidence of early subclinical cardiac injury in patients with left-sided breast cancer receiving hypofractionated radiotherapy after breast conserving surgery, and to investigate the correlation between subclinical cardiac injury and heart dose. We prospectively enrolled 103 breast cancer patients who received whole breast with or without regional nodal irradiation using either deep inspiration breath-hold (DIBH) or free breathing (FB) radiotherapy technique. Cardiac examinations that included N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiogram, and myocardial perfusion imaging were performed routinely before and after radiotherapy. The effects of heart dose, systemic therapy and individual factors (Framingham score) on the incidence of subclinical cardiac events were analyzed. The median age was 48 years. The mean dose (Dmean) of the heart, left anterior descending coronary artery (LAD), left ventricular (LV), and right ventricular (RV) were 402.7 cGy, 1684.9 cGy, 627.2 cGy, and 443.5 cGy, respectively. With a median follow-up of 13.4 months, no patient had clinical cardiac abnormalities. The incidence rates of subclinical cardiac events at 1- 6- and 12-month were 23.5%, 31.6%, and 41.3%, respectively. Univariate analysis showed an increased incidence of subclinical cardiac events with heart Dmean > 4 Gy, LAD V40 > 20%, LV Dmean > 6 Gy, RV Dmean > 7 Gy, or cumulative doses of anthracycline or taxane > 300mg/m2 (All P < 0.05). Anti-HER2 targeted therapy, endocrine therapy, or Framingham score were not associated with the incidence of subclinical cardiac events (all P > 0.05). Multivariate analysis demonstrated that Dmean of LV and RV were independently associated with the increased incidence of subclinical cardiac events. Early subclinical heart injury was found in patients with left-sided breast cancer after hypofractionated radiotherapy. The increased incidence of subclinical cardiac events after radiotherapy was positively associated with the cardiac radiation doses.

High Prevalence of Left Ventricular Non-Compaction and Its Effect on Chemotherapy-Related Cardiac Dysfunction in Patients With Hematological Diseases.

Recent progress in chemotherapy has prolonged the survival of patients with hematological diseases, but has also increased the number of patients with chemotherapy-related cardiac dysfunction (CTRCD). However, the causes of individual variations and risk factors for CTRCD have yet to be fully elucidated. Consecutive echocardiograms of 371 patients were retrospectively evaluated for the presence of left ventricular (LV) non-compaction (LVNC). Individual LV ejection fraction (LVEF) outcome estimates were made using bivariate linear regression with log-transformed duration Akaike information criterion (AIC) model fitting. The prevalence of LVNC was 6-fold higher in patients with hematological diseases than in those with non-hematological diseases (12% vs. 2%; risk ratio 6.1; 95% confidence interval [CI] 2.0, 18.2). Among patients with hematological diseases, the ratio of myeloid diseases was significantly higher in the group with LVNC (P=0.031). Deterioration of LVEF was more severe in patients with than without LVNC (-14.4 percentage points/year [95% CI -21.0, -7.9] vs. -4.6 percentage points/year [95% CI -6.8, -2.4], respectively), even after multivariate adjustment for baseline LVEF, background disease distributions, cumulative anthracycline dose, and other baseline factors. LVNC is relatively prevalent in patients with hematological diseases (particularly myeloid diseases) and can be one of the major risk factors for CTRCD. Detailed cardiac evaluations including LVNC are recommended for patients undergoing chemotherapy.

Clinical prevalence and outcome of cardiovascular events in the first 100 days postallogeneic hematopoietic stem cell transplant.

Recent advances in allogeneic hematopoietic stem cell transplant (HSCT) have allowed us to offer HSCT to older, advanced disease patients with more co-morbidities. Cardiovascular toxicity post-transplant is a major concern due to the increased risk of mortality. Few studies have examined the prevalence of CV events including CAD (MI, angina, PCI, CABG, CHF, arrhythmias), HTN, stroke/TIA, and death in the first 100days post-transplant. We assessed the impact of pretransplant MUGA results in predicting postallogeneic HSCT CV events and overall survival in the first 100days, and whether or not transient anthracycline-induced cardiomyopathy or cumulative anthracycline dose affected overall survival. This retrospective, cohort study included 665 patients with a median age of 52years who underwent HSCT from 2009 to 2015. The most frequent CV event in the first 100days post-HSCT was arrhythmia seen in 2.9% of patients followed up by CHF (12.3%), MI (9%), and angina (8%). Two patients had PCI, and both survived the first 100days. Cardiovascular risk factors predict for a poor MUGA scan but not survival. Higher dose anthracycline pretransplant predicted for a poor outcome. A history of CV disease, MI, or CAD was the most important predictive of CV events, P-value=.00002. 88.6% survived the first 100days. Patients with an EF<50% had a significant likelihood of having a CV event compared to patients with an EF>60% (OR=5.3, 95% CI [1.6-18.1], P=.0219). Cumulative anthracycline dose did not have a significant impact on overall survival.

Early- and late anthracycline-induced cardiac dysfunction: echocardiographic characterization and response to heart failure therapy

BackgroundAnthracycline-induced cardiac dysfunction (ACD) is a notorious side effect of anticancer treatment. It has been described as a phenomenon of a continuous progressive decline of cardiac function, eventually leading to dilated cardiomyopathy (DCM). This progressive nature suggests that patients with a delayed ACD diagnosis have greater compromise of cardiac function and more adverse remodeling, with a poor response to heart failure (HF) treatment. This study aimed to delineate the impact of a delayed ACD diagnosis on echocardiographic characteristics and response to HF treatment.Methods and resultsFrom the population of our cardio-oncology outpatient clinic, 92 ACD patients were included in this study (age 51.6 ± 16.2 years, median cumulative anthracycline dose 329 [200–329] mg/m2), and a median follow-up of 25.0 [9.6–37.2] months after ACD diagnosis. Median time to ACD diagnosis for patients diagnosed early (< 1 year) and late (> 1 year) was 4.0 vs. 47.7 months respectively. There were no echocardiographic differences between patients diagnosed early vs. late (LVEF 43.6 ± 4.9% vs. 43.0 ± 6.2% and iEDV 63.6 vs. 62.9 mL/m2). Eighty-three percent of patients presented with mild LV dysfunction and in 79% the LV was not dilated. Patients diagnosed early were more likely to have (partial) recovery of cardiac function upon HF treatment initiation (p = 0.015).ConclusionsIn the setting of a cardio-oncology outpatient clinic, patients with ACD presented with a hypokinetic non-dilated cardiomyopathy, rather than typical DCM. Timing of ACD diagnosis did not impact HF disease severity. However, in patients receiving an early diagnosis, cardiac function was more likely to recover upon HF treatment.